Heparin was firstly isolated from animal livers by Jay McLean of Johns Hopkins University in 1916, and was identified to be the active ingredient in anti-coagulation (a: Chem. Ind. 1991, 2, 45-50; b: Bull. Johns Hopkins Hosp. 1928, 42, 199), and among glycosaminoglycan (GAG) family, it has the most complex structure. Heparin has been used in clinical treatment of anti-thrombosis and cardiovascular diseases for nearly 60 years, and among its physical activities, the activity in anti-coagulation has been studied and illustrated most intensively and has promoted the use of low molecular heparin (LMWH) as a general anticoagulant, as the substitute of conventional clinical anticoagulants, since 1990's (Blood, 1992, 79, 1-17). Blood coagulation is the consequent of sequential activation of a series of coagulation factors in blood plasma. Finally, inactive thrombin is converted into active thrombin, soluble fibrinogen is partly hydrolyzed and insoluble fibrin is released, resulting in the coagulation of blood. Antithrombin III (ATIII) is the inhibitor of serine protease, in particular thrombin IIa and Xa, in blood coagulation. Although antithrombin III is reacted with thrombin slowly, the reaction rate will increase by thousands of times in the presence of heparin, such that blood coagulation can be inhibited effectively. Natural heparin is mainly extracted from animal viscera and is a complex mixture consisting of different active polysaccharides, and thus its effective dosage cannot be controlled effectively during its application, which may result in risky adverse effects, such as blooding, thrombocytopenia, etc. Meanwhile, heparin molecule may non-specifically bind with blood plasma proteins, resulting in more complex complications. At the end of 1980's, the occurrence of low molecular heparin (LMWH) improves the therapeutic effects of anti-thrombosis. Low molecular heparin is obtained from intact heparin by chemical degradation, enzyme degradation, and gamma-radiation degradation. The trouble is, since their animal sources, heparin and low molecular heparin has the risk of cross virus infection by various species, rendering its application very risky. The most effective means for avoiding such cross virus infection by various species is chemical synthesis of heparin.
Fondaparinux sodium, with chemical name of methyl O-(2-deoxy-6-O-sulfo-2-sulfoamino-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranuronosyl)-(1→4)-O-(2-deoxy-3,6-di-O-sulfo-2-sulfoamino-α-D-glucopyranosyl)-(1→4)-O-(2-O-sulfo-α-L-idopyranuronosyl)-(1→4)-2-deoxy-6-O-sulfo-2-sulfoamino-α-D-glucopyranoside, decasodium salt, belongs to heparin pentasaccharide and was commercialized as anticoagulant in 2001. Its chemical structure is presented in formula 10 as follows:

In the middle of 1980's, Sinay et. al (Carbohydr. Res. 1984, 132, C5-C9, Carbohydr. Res. 1986, 147, 221-236) and Boeckel et. al (J. Carbohydr. Chem. 1985, 4, 293-321.) successively achieved the fully synthesis of anticoagulant pentasaccharide without capped methyl. Fully protected pentasaccharide is converted into the final product pentasaccharide via the reaction schemes represented by the following formulae 1-5. The reaction steps includes: 1. saponification of the ester group, 2. sulfation of the hydroxyl group, 3. hydrogenation reduction of azido or carboxybenzyl-protected amino group to unprotected amino group with Pd/C, and subsequent deprotection of benzyl protective group on hydroxyl group, and 4. selective sulfation of amino group.

In the above mentioned conversion of the pentasaccharide, the reduction of azido group to amino group is very rapid, and it tends to successively carry out adverse reaction with reductive terminal aldehyde group of the hemiacetal tautomer of the pentasaccharide, generating stable dimmers or trimers, resulting in extremely poor reaction efficiency.
In the process of resolving the problem, it is found that the problem of the formation of dimmers and trimers during the reduction in the synthesis process can be avoided by using methyl-capped pentasaccharide (Carbohydr. Res. 1987. 167, 67-75), such that the hydrogenation reduction can be carried out with nearly quantitative yield, with a reaction scheme as presented in following scheme 6-10. Its synthesis scheme is substantially identical to that using uncapped pentasaccharide as the raw material, and includes the following 4 steps: 1. saponification of the ester group of the fully protected pentasaccharide, generating five unprotected hydroxyl groups to be subjected to sulfation, 2. sulfation of the hydroxyl group, 3. hydrogenation reduction of azido-protected or benzylcarbonyl-protected amino group to unprotected amino group with Pd/C, and subsequent deprotection of hydroxyl group, and 4. selective sulfation of amino group, in order to obtain the product fondaparinux sodium.

WO2003022860 and WO2010040880 also employ similar method.
Tests on biological activity demonstrate that, methyl protection of reduction terminal has no influence on the biological activity of heparin pentasaccharide, and thus the protection strategy using methyl capping becomes a routine strategy for the synthesis of heparin oligomeric molecules.
The method according to the prior art requires simultaneous conversion of benzyl-protected hydroxyl and azido (or benzoxylcarboxyl-protected amino) into unprotected hydroxyl and amino via hydrogenation, wherein the intermediate has poor stability and is hard to be purified. Furthermore, the final step requires selective sulfation of all three amino groups among six unprotected hydroxyl and three unprotected amino. The yield of the reaction is very poor, due to poor selectively of the reaction, and the final product is hard to be purified.
The process according to the present invention employs a highly efficient reduction process to reduce azido group into unprotected amino group firstly, after removing the ester group of fully protected pentasaccharide. The crude intermediate has high purity, and can be used in the next step without purification. Subsequently, all of unprotected hydroxyl groups and amino groups are sulfated. It has high efficiency, and the remaining benzyl group facilitates the purification of such intermediate. Finally, all of the benzyl groups are removed via hydrogenation, in order to obtain the final product.